Network Pharmacology/Metabolomics‐Based Validation of AMPK and PI3K/AKT Signaling Pathway as a Central Role of Shengqi Fuzheng Injection Regulation of Mitochondrial Dysfunction in Cancer‐Related Fatigue

Abstract

Chinese herbal medicines have multiple targets and properties, and their use in multidisciplinary cancer therapies has consequently received increasing attention. Here, we have investigated the possible active ingredients associated with cancer-related fatigue (CRF) in the Shengqi Fuzheng Injection (SFI). In vitro cell models were used to measure the regulation effects of SFI on CRF. Metabolomic analysis was used to identify the potential genes and pathways in C2C12 mouse myoblasts treated with SFI, and the interaction of compounds and CRF targets was predicted using network pharmacology and molecular docking analyses. The putative pathways were further verified using immuno-blotting assays. The results showed that SFI significantly inhibited muscle cell apoptosis and increased the mitochondrial membrane potential of muscle cells. The network pharmacology analysis results identified 36 candidate compounds, and 244 potential targets were yielded by SFI, and they shared 10 key targets associated with cancer-related fatigue. According to the enrichment analysis and experimental validation, SFI might ameliorate muscle cell mitochondrial function by activating AMPK and inhibiting the PI3K/Akt signaling pathways, and the expression changes of mitochondrial metabolic enzymes MnSOD and apoptosis-associated proteins Bax and Bcl-2 were also triggered. The functions and mechanisms of SFI in anticancer-related fatigue were found here to be at least partly due to the targeting of the AMPK and PI3K/Akt signaling pathways, and this has highlighted new potential applications for network pharmacology when researching Chinese Medicines.

Metabolomics and integrated network pharmacology analysis reveal SNKAF decoction suppresses cell proliferation and induced cell apoptisis in hepatocellular carcinoma via PI3K/Akt/P53/FoxO signaling axis

“…The mechanisms are closely associated with the pathological cell cycle and death changes of HCC. The PI3K/Akt pathway exerts a significant effect on cell survival, proliferation, migration, metabolism, and apoptosis among different tumor kinds, including HCC [ 35 , 50 ]. The compounds of SNKAF were boosted upon the binding of the signaling molecules and consequently provoked the related receptors at the surface of the cell membrane.…”

“…The subjection of target genes to the Database for Annotation, Visualization, and Integrated Discovery (DAID, https://david.ncifcrf.gov/ ) and the Comparative Toxic Genetics Database (CTD, http://ctdbase.org/ ) was made to implement Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment for functional enrichment analysis. The clusterProfiler software package for R3.5.3 was utilized to evaluate the hidden biological functions, and P- value < 0.05 suggested greater enrichment [ 35 ].…”

Integrated metabolomics, network pharmacology and biological verification to reveal the mechanisms of Nauclea officinalis treatment of LPS-induced acute lung injury

“…The compounds with OB ≥ 25% were selected as the active compounds of DM for further analysis. Next, the component targets were collected from BATMAN-TCM ( http://bionet.ncpsb.org/batman-tcm/ ) [ 24 ], DrugBank ( https://www.drugbank.ca/ ) and Swiss Target Prediction ( http://www.swisstargetprediction.ch/ ) databases [ 25 ]. The SMILES of each compound was searched in PubChem ( https://pubchem.ncbi.nlm.nih.gov/ ) and imported into Swiss Target Prediction ( http://www.swisstargetprediction.ch/ ) to acquire the related targets.…”

An integrated network pharmacology and metabolomics approach to reveal the immunomodulatory mechanism of Brassica rapa L. (Tibetan Turnip) in fatigue mice

“…Network pharmacology and metabolomics are powerful tools for evaluating the pharmacological effects of phytopharmaceuticals, 15,16 such as in the pathogenesis of diseaseinduced chronic fatigue. 17 Network pharmacology is an approach to revealing the potential interactions among diseases, genes, targets, and medicines, based on the theory of system biology, as well as multidirectional pharmacology. However, the potential accompanying issues, including the accuracy, reliability, and completeness of used data, still cannot be easily ignored.…”